Acute surgical pain management in children is best addressed by a dedicated pain management team. Although PCA with opioids forms the main modality of analgesia, regional techniques have gained popularity. PCA by proxy and PCA basal infusions enhance analgesia but carry a risk for respiratory depression and sedation. Efficient prevention of opioid-induced respiratory depression requires the use of appropriate monitoring including pulsoximetry and respiratory rate, clinical sedation scoring system, repeated assessment by the pain team, early intervention protocols, and use of nonopioid adjuncts like IV or oral acetaminophen and ketorolac/NSAIDs. Thalamocortical connections underpinning the neuroanatomy of pain appear between 20 and 30 weeks of gestational age, and the physiological mechanisms for pain perception become established by early second trimester. There are long-lasting effects of pain experienced in early life underscoring the need to treat surgical pain in fetuses, premature infants, and neonates. In contrast, there is a growing body of evidence in animal models implicating opioids in adversely altering neuronal proliferation in the developing brain and clinical studies where in morphine sedation in the neonatal period was found to decrease visual motor integration in childhood, suggesting a potential for neurocognitive sequelae. Ongoing research provides hope that future integration of pharmacogenetics, metabolomics, and proteomics in clinical decision and analgesic selection/dosing processes will maximize analgesia and minimize adverse effects.